Identifying which interventions work best for who is a critical, yet unresolved, issue in prevention science. There has been a paucity of research on underlying mechanisms by which change occurs in prevention models with early school-aged children in spite of growing evidence that a high level of brain plasticity characterizes the early stages of development, providing an optimal window of opportunity. Moreover, no school-based prevention trials have utilized a model of intervention responsively that incorporates the new generation of scientific disciplines, thus limiting the ability to address these issues in an integrated and translational fashion. Existing studies also lack measures reflective of processes (e.g., neurocognition and physiology) shown to modulate skills (e.g., inhibitory control and emotion regulation) that have repeatedly been implicated in high-risk behaviors. To fill these gaps in knowledge, the proposed 5-year R01 study would be the first in-depth school-based intervention trial that infuses relevant aspects of cognitive neuroscience with existing theories of developmental psychology and prevention science. The ultimate goal is to identify underlying conditions (inhibitory control and emotional regulation) that may serve to both mediate and moderate intervention effects in the early years of schooling. Accordingly, we propose to conduct a theory-driven examination of Promoting Alternative Thinking Strategies (PATHS), an evidence- based model with replicated outcome effects, to understand how the intervention works and for whom. The PATHS program will be implemented in kindergarten classrooms through first grade in 2-3 schools (Ne150) with an additional 2-3 schools as an active control condition (Ne150) using a randomized trial design. These Baltimore City schools serve a demographically mixed community with relatively low academic achievement and a high level of behavioral problems. Two cohorts of kindergartners will receive PATHS for two consecutive years, while the control school will receive professional development workshops as well as incentives, testing, and observations similar to the experimental schools. Pretesting will be conducted in the fall of K to assess background and behavioral factors, cognitive functioning, and emotional regulation (measured by physiological stress reactivity). Measures will be repeated once at the completion of the school year, again at the end of first grade, and then a follow-up at 6 months following program completion during second grade for each cohort. Directly following from the recent conceptual and empirical work of the study team and others, this study represents a substantial innovation with implications for reducing behavioral disorders in youths. It is critical to identify underlying bases for individual differences in intervention responsively to tailor preventive approaches to specific needs of subgroups, thereby enhancing efficiency, cost-effectiveness, and maximization of impact. PUBLIC HEALTH RELEVANCE: Collaborative transdisciplinary work integrating developmental psychopathology, neuroscience, and prevention science promises to significantly advance not only an etiological understanding of risk behaviors but also of variability in intervention efficacy via the use of a multiple-levels approach. There is a clear scientific need to examine both mediators and moderators of preventive intervention effects to better understand their mechanisms of action. The proposed study will identify underlying conditions that mediate ultimate outcomes of a model preventive intervention to substantially improve our ability to monitor program effects and target program components. Use of a multiple-levels approach such as the one proposed herein offers optimism that preventive intervention research will continue to advance in terms of its sophistication and comprehensiveness, and translational efforts to develop interventions that promote resilient functioning will be fostered. Ultimately, knowledge generated from this study will highlight areas in need of improvement for a class of preventive interventions that are used in many U.S. elementary schools, as well as the design of new components that are better suited to various subgroups.